Status Epilepticus (SE) is recognized as a medical emergency, and is associated with significant morbidity and mortality. Little is known about factors important in the pathophysiology of SE, perhaps due to a shortage of animal models available to study significant physiological determinants of this disorder. The goal of this proposal is to investigate factors important in development, maintenance, and termination of the sustained seizure discharges of SE in a newly developed in vitro animal model of sustained seizure discharge. A combined hippocampal-parahippocampal brain slice preparation will be employed as a model supporting the sustained seizure discharges of SE, and physiological and pharmacological mechanisms important in development, maintenance, and termination of these sustained epileptiform discharges will be studied using this preparation. Sustained epileptiform discharges will be elicited through stimulation of the Schaeffer collateral fiber pathway within the hippocampus, and subsequent development of activity will be monitored using extra- and intracellular neurophysiological recording techniques. The role of activation of excitatory amino acid receptors in triggering these long duration epileptiform discharges will be explored, as will the anticonvulsant pharmacology relevant to control of these discharges. The behavior of various neuronal populations within the hippocampal-parahippocampal slice will be studied during the development of sustained seizure discharges, using intracellular current- and voltage-clamp recording. This should enable determination of the contribution of excitatory and inhibitory synaptic plasticity to sustained seizure activity, and to ascertain the nature and voltage-dependence of the synaptic and intrinsic conductances activated during epileptiform discharges, and how alterations in these conductances contribute to ongoing epileptogenesis. The advantages of the brain slice and acutely isolated neuron preparations include superior access to and control of the extracellular environment, improved stability of the tissue, and visibility and accessibility of central structures facilitating physiological recording. Studies combining these advantages with the unique properties of the hippocampal-parahippocampal slice, which supports sustained epileptiform discharges of sufficient duration to satisfy the definition of SE, and hence are more closely comparable to discharges seen in vivo, could provide new insight into seizure initiation, maintenance, and termination mechanisms important in understanding and controlling SE. Findings from these studies could have direct relevance to our understanding of the aetiology of this debilitating neurologic disorder, and could aid, in combination with human studies on the pathophysiology of SE, in the development of novel therapeutic agents and strategies for control of SE.